1. Field of the Invention
This invention relates to a series of anthranilic acid compounds that are useful in the treatment of hepatitis C infection.
2. Related Background Art
Hepatitis C is a common infection that can lead to chronic hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma. Infection with the hepatitis C virus (HCV) leads to chronic hepatitis in at least 85% of cases. It is the leading reason for liver transplantation, and is responsible for at least 10,000 deaths annually in the United States (Hepatology, 1997, 26 (Suppl. 1), 2S-10S).
The hepatitis C virus is a member of the Flaviviridae family. The genome of HCV is a positive strand, single-stranded linear (Hepatology, 1997, 26 (Suppl. 1), 11S-14S). HCV displays extensive genetic heterogeneity; at least six genotypes and more than 50 subtypes have been identified.
There is currently no effective vaccine to prevent HCV infection. The only therapy currently available is treatment with interferon-α (INF-α or combination therapy of INF-α with the nucleoside analog ribavirin (Antiviral Chemistry and Chemotherapy, 1997, 8, 281-301). However, only about 40% of treated patients develop a sustained response. Thus, there remains a need for more effective anti-HCV therapeutic agents.
Following infection by HCV, the viral RNA is translated into a polyprotein. This approximately 3,000 residue polyprotein is subsequently cleaved into individual proteins by host peptidases, as well as virally encoded proteases. The HCV genome encodes at least 10 structural (required for viral assembly) and nonstructural proteins (required for replication). Some of the nonstructural proteins include: NS2, NS3, NS4A, NS4B, NS5A, and NS5B (J. General Virology, 2000, 81, 1631-1648). NS5B is a RNA dependent RNA polymerase that is essential for viral replication. In positive stranded RNA viruses, such as HCV, RNA is the sole genetic material. Since mammal host cells ordinarily lack RNA-dependent RNA polymerase activity, the positive stranded RNA viruses encode their own replicative polymerase (NS5B in the case of HCV), which is essential for the production of virion progeny. The inhibition of NS5B activity, therefore, provides choice target for HCV drug design.